Submissions for variant NM_000249.4(MLH1):c.2080_2081inv (p.Glu694Ser)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219102	SCV000274942	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-11	criteria provided, single submitter	clinical testing	The c.2080_2081delGAinsTC variant (also known as p.E694S), located in coding exon 18 of the MLH1 gene, results from an in-frame deletion of GA and insertion of TC at nucleotide positions 2080 to 2081. This results in the substitution of the glutamic acid residue for a serine residue at codon 694, an amino acid with similar properties. This alteration has been identified in a patient whose colon tumor demonstrated microsatellite instability, absent MLH1 staining by IHC, and loss of heterozygosity (Kim JE et al. Exp Mol Med, 2021 Mar;53:446-456). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000589333	SCV000569500	uncertain significance	not provided	2023-01-28	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter protein structure/function; Observed in an individual with sarcoma who also carried a pathogenic variant in BRCA2 (Varga et al., 2015); This variant is associated with the following publications: (PMID: 23695190, 25712765, 12799449, 20533529, 22753075)
Invitae	RCV000556535	SCV000625123	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with serine, which is neutral and polar, at codon 694 of the MLH1 protein (p.Glu694Ser). This variant is present in population databases (no rsID available, gnomAD 0.2%). This missense change has been observed in individual(s) with sarcoma (PMID: 25712765). ClinVar contains an entry for this variant (Variation ID: 455415). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000219102	SCV000684797	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-25	criteria provided, single submitter	clinical testing	This variant causes a deletion of GA and insertion of TC at nucleotide positions 2080 and 2081 in exon 18 of the MLH1 gene, which replaces glutamic acid with serine at codon 694 of the MLH1 protein. This substitution changes two basepairs, c.2080G>T and c.2081A>C, which together changes the codon for glutamic acid (GAG) to one for serine (TCG). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early onset, microsatellite unstable colorectal cancer (PMID: 33753878), as well as in an individual affected with sarcoma who also carried a pathogenic variant in the BRCA2 gene (PMID: 25712765). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855650	SCV000696143	uncertain significance	not specified	2023-10-16	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.2080_2081delinsTC (p.Glu694Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. This variant is reported as two separate single nucleotide changes in gnomAD, with both variants found in the same subpopulations with the same number of occurrences, and read data demonstrating that both of these SNPs occurred together in cis, in 3 cases. Therefore the variant allele was found at a frequency of 2e-05 in 251054 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2080_2081delinsTC has been reported in the literature in an individual affected with sarcoma, who also carried a BRCA2 pathogenic allele (Varga_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25712765). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003459173	SCV004192980	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-06-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003719	SCV004843271	uncertain significance	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This variant causes a deletion of GA and insertion of TC at nucleotide positions 2080 and 2081 in exon 18 of the MLH1 gene, which replaces glutamic acid with serine at codon 694 of the MLH1 protein. This substitution changes two basepairs, c.2080G>T and c.2081A>C, which together changes the codon for glutamic acid (GAG) to one for serine (TCG). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early onset, microsatellite unstable colorectal cancer (PMID: 33753878), as well as in an individual affected with sarcoma who also carried a pathogenic variant in the BRCA2 gene (PMID: 25712765). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.